Summary: Researchers report a major new insight into Alzheimer’s disease: the brain’s immune cells accumulate cancer-associated mutations with age, and these mutated cells appear to promote neuroinflammation and neuronal death. The mutations are the same kinds found in blood cancers such as leukemia, suggesting potential new diagnostic and treatment approaches that repurpose existing oncology tools.
A study led by investigators at Boston Children’s Hospital shows that microglia—resident immune cells of the brain—harbor somatic mutations in cancer driver genes. Rather than forming tumors, these mutated microglia adopt inflammatory and proliferative states that damage neurons. Because the same mutations can be detected in blood cells, the findings raise the possibility of blood-based genetic screening and the targeted use of approved cancer drugs to slow or prevent Alzheimer’s disease.
Key Findings
- Repurposing cancer drugs: The mutations identified in Alzheimer’s brain tissue match those driving some blood cancers, implying that drugs already approved for hematologic malignancies might be repurposed to target the mutant immune cells that contribute to neurodegeneration.
- New diagnostic potential: Because the same somatic mutations are detectable in patients’ blood, simple genetic screens could in the future identify individuals who are at elevated risk for Alzheimer’s years before clinical symptoms appear.
- Somatic mosaicism matters: The work strengthens evidence that postnatal, or somatic, mutations accumulating in tissues (somatic mosaicism) can play a causal role in age-related diseases beyond cancer, including Alzheimer’s disease.
Source: Boston Children’s Hospital
As people age, cells gradually acquire genetic changes. In a Cell paper, researchers from Boston Children’s Hospital report deep sequencing of cancer-associated genes across hundreds of brain samples and matched blood, revealing enrichment of somatic single-nucleotide variants (sSNVs) and copy-number changes in microglia-like brain macrophages from Alzheimer’s patients. These alterations were especially concentrated in genes previously linked to clonal hematopoiesis.
The study was led by Christopher Walsh, MD, PhD, Chief of the Division of Genetics and Genomics at Boston Children’s, with major contributions from Alice Eunjung Lee, PhD, and August Yue Huang, PhD. All are affiliated with Harvard Medical School and the Broad Institute.
To compare Alzheimer’s and control brains, the team sequenced 149 cancer-associated genes in tissue from 190 donated Alzheimer’s brains and 121 healthy control brains. The Alzheimer’s samples showed more single-letter DNA changes, concentrated in five cancer driver genes. That pattern indicates selective accumulation of mutations in specific genes within the microglial population.
Microglia act as the brain’s immune sentinels and scavengers. Unlike circulating immune cells, microglia are resident in the central nervous system. The researchers unexpectedly found that some of the cancer-associated mutations present in the brain were also present in the blood of the same individuals. This finding suggests a likely hematopoietic origin for many of the mutant microglial-like cells observed in the brain.
The authors propose a model in which aging or injury weakens the blood-brain barrier, permitting blood-derived immune cells carrying driver mutations to enter the brain and adopt microglia-like roles. In parallel, brain protein aggregates trigger microglial activation and proliferation. Cells carrying mutations that confer a growth or survival advantage can clonally expand and dominate the niche, but they also produce a more inflammatory, neurotoxic environment that leads to neuronal loss and the progression of Alzheimer’s pathology.
Because direct access to living brain tissue is limited, the discovery that the same driver mutations are present in peripheral blood opens the door to developing blood-based genetic screens. Such tests could identify people with clonal hematopoietic mutations associated with increased Alzheimer’s risk, enabling earlier monitoring or intervention.
In a follow-up preprint, Huang and Lee showed that the presence of cancer driver variants in blood increased Alzheimer’s risk independently of the well-known APOE4 genetic risk factor, further supporting the clinical relevance of these somatic changes.
Funding: The work involved collaborators at the Icahn School of Medicine at Mount Sinai and received support from the Howard Hughes Medical Institute, the National Institute on Aging, the NIH Common Fund through the Somatic Mosaicism Across Human Tissues (SMaHT) consortium, and the Suh Kyungbae Foundation.
Key Questions Answered:
A: No. Alzheimer’s does not form a tumor. Rather, it appears to share a mechanism with blood cancers: somatic driver mutations that enable certain cells to outcompete others. In Alzheimer’s, the dominant cells become toxic to neurons rather than forming a mass.
A: Not yet. These findings are currently at the research stage. The investigators are exploring development of blood-based genetic screens that could one day be used clinically to assess risk.
A: Previously, the relevant cellular targets and mutations were not known. With specific driver genes now implicated, precision approaches could selectively target mutant immune cells while sparing healthy cells, making repurposing of certain oncology drugs a more feasible strategy.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- The original journal paper was reviewed in full by the editorial team.
- Additional context was provided by staff contributors.
About this genetics, Alzheimer’s disease, and cancer research news
Author: Joelle Zaslow
Source: Boston Children’s Hospital
Contact: Joelle Zaslow – Boston Children’s Hospital
Image: Image credit: Neuroscience News
Original Research: Open access. Title: “Somatic cancer variants enriched in Alzheimer’s disease microglia-like cells drive inflammatory and proliferative states” by August Yue Huang et al., published in Cell. DOI: 10.1016/j.cell.2026.03.040
Abstract
Somatic cancer variants enriched in Alzheimer’s disease microglia-like cells drive inflammatory and proliferative states
Alzheimer’s disease (AD) is a neurodegenerative disorder marked by microglia-driven neuroinflammation. Deep (>1,000×) targeted sequencing of 311 brain samples revealed enrichment of somatic single-nucleotide variants (sSNVs) in cancer driver genes in AD brains, particularly in genes linked to clonal hematopoiesis. These sSNVs were associated with clonal expansion and were present in microglia-like brain macrophages across multiple brain regions as well as in paired blood samples, pointing to a likely hematopoietic origin.
Single-nucleus RNA sequencing of additional AD and control brains found increased somatic copy-number variants associated with clonal hematopoiesis in microglia-like cells from AD tissue. Single-cell multi-omic analyses showed that cells carrying sSNVs and sCNVs displayed inflammatory and proliferative transcriptional signatures characteristic of disease-associated microglia. These signatures were reproduced in induced pluripotent stem cell-derived microglia-like cells engineered to carry TET2, ASXL1, or DNMT3A variants. The findings indicate that clonal somatic driver variants in microglia-like brain macrophages are enriched in AD and may promote neuroinflammation and neurodegeneration.